1,3,3-(Trisubstituted)cyclohex-1-ene dimers and related compounds

ABSTRACT

This invention relates to certain 1,3,3-(trisubstituted)cyclohex-1-ene dimers and related compounds which are useful in treating allergic and inflammatory diseases and for inhibiting the production of Tumor Necrosis Factor (TNF).

FIELD OF INVENTION

The present invention relates to novel1,3,3-(trisubstituted)cyclohex-1-ene dimers and related compounds,pharmaceutical compositions containing these compounds, and their use intreating allergic and inflammatory diseases and for inhibiting theproduction of Tumor Necrosis Factor (TNF).

BACKGROUND OF THE INVENTION

Bronchial asthma is a complex, multifactorial disease characterized byreversible narrowing of the airway and hyperreactivity of therespiratory tract to external stimuli.

Identification of novel therapeutic agents for asthma is made difficultby the fact that multiple mediators are responsible for the developmentof the disease. Thus, it seems unlikely that eliminating the effects ofa single mediator will have a substantial effect on all three componentsof chronic asthma. An alternative to the "mediator approach" is toregulate the activity of the cells responsible for the pathophysiologyof the disease.

One such way is by elevating levels of cAMP (adenosine cyclic3',5'-monophosphate). Cyclic AMP has been shown to be a second messengermediating the biologic responses to a wide range of hormones,neurotransmitters and drugs; Krebs Endocrinology Proceedings of the 4thInternational Congress Excerpta Medica, 17-29, 1973!. When theappropriate agonist binds to specific cell surface receptors, adenylatecyclase is activated, which converts Mg⁺² -ATP to cAMP at an acceleratedrate.

Cyclic AMP modulates the activity of most, if not all, of the cells thatcontribute to the pathophysiology of extrinsic (allergic) asthma. Assuch, an elevation of cAMP would produce beneficial effectsincluding: 1) airway smooth muscle relaxation, 2) inhibition of mastcell mediator release, 3) suppression of neutrophil degranulation, 4)inhibition of basophil degranulation, and 5) inhibition of monocyte andmacrophage activation. Hence, compounds that activate adenylate cyclaseor inhibit phosphodiesterase should be effective in suppressing theinappropriate activation of airway smooth muscle and a wide variety ofinflammatory cells. The principal cellular mechanism for theinactivation of cAMP is hydrolysis of the 3'-phosphodiester bond by oneor more of a family of isozymes referred to as cyclic nucleotidephosphodiesterases (PDEs).

It has now been shown that a distinct cyclic nucleotidephosphodiesterase PDE) isozyme, PDE IV, is responsible for cAMPbreakdown in airway smooth muscle and inflammatory cells. Torphy,"Phosphodiesterase Isozymes: Potential Targets for Novel Anti-asthmaticAgents" in New Drugs for Asthma, Barnes, ed. IBC Technical ServicesLtd., 1989!. Research indicates that inhibition of this enzyme not onlyproduces airway smooth muscle relaxation, but also suppressesdegranulation of mast cells, basophils and neutrophils along withinhibiting the activation of monocytes and neutrophils. Moreover, thebeneficial effects of PDE IV inhibitors are markedly potentiated whenadenylate cyclase activity of target cells is elevated by appropriatehormones or autocoids, as would be the case in vivo. Thus PDE IVinhibitors would be effective in the asthmatic lung, where levels ofprostaglandin E₂ and prostacyclin (activators of adenylate cyclase) areelevated. Such compounds would offer a unique approach toward thepharmacotherapy of bronchial asthma and possess significant therapeuticadvantages over agents currently on the market.

The compounds of this invention also inhibit the production of TumorNecrosis Factor (TNF), a serum glycoprotein. Excessive or unregulatedTNF production has been implicated in mediating or exacerbating a numberof diseases including rheumatoid arthritis, rheumatoid spondylitis,osteoarthritis, gouty arthritis and other arthritic conditions; sepsis,septic shock, endotoxic shock, gram negative sepsis, toxic shocksyndrome, adult respiratory distress syndrome, cerebral malaria, chronicpulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, boneresorption diseases, reperfusion injury, graft vs. host reaction,allograft rejections, fever and myalgias due to infection, such asinfluenza, cachexia secondary to infection or malignancy, cachexiasecondary to human acquired immune deficiency syndrome (AIDS), AIDS, ARC(AIDS related complex), keloid formation, scar tissue formation, Crohn'sdisease, ulcerative colitis, or pyresis, in addition to a number ofautoimmune diseases, such as multiple sclerosis, autoimmune diabetes andsystemic lupus erythematosis.

AIDS results from the infection of T lymphocytes with HumanImmunodeficiency Virus (HIV). At least three types or strains of HIVhave been identified, i.e., HIV-1, HIV-2 and HIV-3. As a consequence ofHIV infection, T-cell-mediated immunity is impaired and infectedindividuals manifest severe opportunistic infections and/or unusualneoplasms. HIV entry into the T lymphocyte requires T lymphocyteactivation. Viruses such as HIV-1 or HIV-2 infect T lymphocytes after Tcell activation and such virus protein expression and/or replication ismediated or maintained by such T cell activation. Once an activated Tlymphocyte is infected with HIV, the T lymphocyte must continue to bemaintained in an activated state to permit HIV gene expression and/orHIV replication.

Cytokines, specifically TNF, are implicated in activated T-cell-mediatedHIV protein expression and/or virus replication by playing a role inmaintaining T lymphocyte activation. Therefore, interference withcytokine activity such as by inhibition of cytokine production, notablyTNF, in an HIV-infected individual aids in limiting the maintenance of Tcell activation, thereby reducing the progression of HIV infectivity topreviously uninfected cells which results in a slowing or elimination ofthe progression of immune dysfunction caused by HIV infection.Monocytes, macrophages, and related cells, such as kupffer and glialcells, have also been implicated in maintenance of the HIV infection.These cells, like T cells, are targets for viral replication and thelevel of viral replication is dependent upon the activation state of thecells. See Rosenberg et al, The Immunopathogenesis of HIV Infection,Advances in Immunology, Vol. 57, 1989!. Monokines, such as TNF, havebeen shown to activate HIV replication in monocytes and/or macrophagesSee Poli et al, Proc. Natl. Acad. Sci., 87:782-784, 1990!, therefore,inhibition of monokine production or activity aids in limiting HIVprogression as stated above for T cells.

TNF has also been implicated in various roles with other viralinfections, such as the cytomegalovirus (CMV), influenza virus,adenovirus, and the herpes virus for similar reasons as those noted.

TNF is also associated with yeast and fungal infections. SpecificallyCandida albicans has been shown to induce TNF production in vitro inhuman monocytes and natural killer cells. See Riipi et al, Infection andImmunity, 58(9):2750-54, 1990; and Jafari et al, Journal of InfectiousDiseases, 164:389-95, 1991. See also Wasan et al., Antimicrobial Agentsand Chemotherapy, 35,(10):2046-48, 1991; and Luke et al., Journal ofInfectious Diseases, 162:211-214,1990!.

The ability to control the adverse effects of TNF is furthered by theuse of the compounds which inhibit TNF in mammals who are in need ofsuch use. There remains a need for compounds which are useful intreating TNF-mediated disease states which are exacerbated or caused bythe excessive and/or unregulated production of TNF.

SUMMARY OF THE INVENTION

The compounds of Formula (I) are represented by the following structure:##STR1## wherein: R₁ is --(CR₄ R₅)_(n) C(O)O(CR₄ R₅)_(m) R₆, --(CR₄R₅)_(n) C(O)NR₄ (CR₄ R₅)_(m) R₆, --(CR₄ R₅)_(n) O(CR₄ R₅)_(m) R₆, or--(CR₄ R₅)_(r) R₆ wherein the alkyl moieties are unsubstituted orsubstituted with one or more halogens;

m is 0 to 2;

n is 0 to 4;

r is 0 to 6;

R₄ and R₅ are independently hydrogen or a C₁₋₂ alkyl;

R₆ is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl,aryloxyC₁₋₃ alkyl, halo substituted aryloxyC₁₋₃ alkyl, indanyl, indenyl,C₇₋₁₁ polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl,pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl,C₃₋₆ cycloalkyl, or a C₄₋₆ cycloalkyl containing one or two unsaturatedbonds, wherein the cycloalkyl or heterocyclic moiety may beunsubstituted or substituted by 1 to 3 methyl groups, one ethyl group oran hydroxyl group;

provided that:

a) when R₆ is hydroxyl, then m is 2; or

b) when R₆ is hydroxyl, then r is 2 to 6; or

c) when R₆ is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl,2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or

d) when R₆ is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl,2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then r is 1 to 6;

e) when n is 1 and m is 0, then R₆ is other than H in --(CR₄ R₅)_(n)O(CR₄ R₅)_(m) R₆ ;

X is YR₂, fluorine, NR₄ R₅, or formyl amine;

Y is O or S(O)_(m') ;

m' is 0, 1, or 2;

X₂ is O or NR₈ ;

X₃ is hydrogen or X;

R₂ is --CH₃ or --CH₂ CH₃ unsubstituted or substituted by 1 or morehalogens;

s is 0 to 4;

W is alkyl of 2 to 6 carbons, alkenyl of 2 to 6 carbons or alkynyl of 2to 6 carbons;

Z is S(O)_(m') R₉, OS(O)₂ R₉, OR₉, OC(O)NR₇ R₇, OC(O)(O)_(q) R₇, O(CR₄R₅)_(n) OR₉, or NR₉ R₉ ;

q is 0 or 1;

R₇ is hydrogen or R₉ ;

R₈ is hydrogen or C₁₋₄ alkyl unsubstituted or substituted by one tothree fluorines, or when R₈ and R₁₀ are as --NR₈ R₁₀ they may togetherwith the nitrogen form a a 5 to 7 membered ring comprised only of carbonatoms or carbon atoms and at least one heteroatom selected from O, N, orS;

R₉ is C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₃₋₇ cycloalkyl, C₄₋₆ cycloalkenyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, each of which may beunsubstituted or substituted by one or more fluorine atoms, or two R₉terms appearing as NR₉ R₉ may together with the nitrogen form a 5 to 7membered ring comprised only of carbon atoms or carbon atoms and atleast one heteroatom selected from O, N, or S;

R₁₀ is OR₈ or R₈ ;

provided that:

f) when q is 1 in OC(O)(O)_(q) R₇, then R₇ is not hydrogen; or thepharmaceutically acceptable salts thereof.

Another set of compounds of this invention are represented by Formula(II): ##STR2## wherein: R₁ is --(CR₄ R₅)_(n) C(O)O(CR₄ R₅)_(m) R₆,--(CR₄ R₅)_(n) C(O)NR₄ (CR₄ R₅)_(m) R₆, --(CR₄ R₅)_(n) O(CR₄ R₅)_(m) R₆,or --(CR₄ R₅)_(r) R₆ wherein the alkyl moieties are unsubstituted orsubstituted with one or more halogens;

m is 0 to 2;

n is 0 to 4;

r is 0 to 6;

R₄ and R₅ are independently hydrogen or a C₁₋₂ alkyl;

R₆ is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl,aryloxyC₁₋₃ alkyl, halo substituted aryloxyC₁₋₃ alkyl, indanyl, indenyl,C₇₋₁₁ polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl,pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl,C₃₋₆ cycloalkyl, or a C₄₋₆ cycloalkyl containing one or two unsaturatedbonds, wherein the cycloalkyl or heterocyclic moiety may beunsubstituted or substituted by 1 to 3 methyl groups, one ethyl group oran hydroxyl group;

provided that:

a) when R₆ is hydroxyl, then m is 2; or

b) when R₆ is hydroxyl, then r is 2 to 6; or

c) when R₆ is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl,2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or

d) when R₆ is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl,2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then r is 1 to 6;

e) when n is 1 and m is 0, then R₆ is other than H in --(CR₄ R₅)_(n)O(CR₄ R₅)_(m) R₆ ;

X is YR₂, fluorine, NR₄ R₅, or formyl amine;

Y is O or S(O)_(m') ;

m' is 0, 1, or 2;

X₂ is O or NR₈ ;

X₃ is hydrogen or X;

R₂ is --CH₃ or --CH₂ CH₃ unsubstituted or substituted by 1 or morehalogens;

s is 0 to 4;

W is alkyl of 2 to 6 carbons, alkenyl of 2 to 6 carbons or alkynyl of 2to 6 carbons;

Z is NHR₁₄, S(O)_(m') R₉, OS(O)₂ R₉, OR₉, OC(O)NR₇ R₇, OC(O)(O)_(q) R₇,O(CR₄ R₅)_(n) OR₉, or NR₉ R₉ ;

Z' is C(Y')R₁₄, C(O)OR₁₄, C(Y')NR₁₀ R₁₄, C(NR₁₀)NR₁₀ R₁₄, CN,C(NOR₈)R₁₄, C(NOR₁₄)R₈, C(NR₈)NR₁₀ R₁₄, C(NR₁₄)NR₈ R₈ C(NCN)NR₁₀ R₁₄,C(NCN)SR₁₁, (2-, 4- or 5-imidazolyl), (3-, 4- or 5-pyrazolyl), (4- or5-triazolyl 1,2,3!), (3- or 5-triazolyl 1,2,4!), (5-tetrazolyl), (2-, 4-or 5-oxazolyl), (3-, 4- or 5-isoxazolyl), (3- or 5-oxadiazolyl 1,2,4!),(2-oxadiazolyl 1,3,4!), (2-thiadiazolyl 1,3,4!), (2-, 4-, or5-thiazolyl), (2-, 4-, or 5-oxazolidinyl), (2-, 4-, or 5-thiazolidinyl),or (2-, 4-, or 5-imidazolidinyl); wherein all of the heterocylic ringsystems may be optionally substituted one or more times by R₁₄ ;

Y' is O or S;

q is 0 or 1;

R₇ is hydrogen or R₉ ;

R₈ is hydrogen or C₁₋₄ alkyl unsubstituted or substituted by one tothree fluorines, or when R₈ and R₁₀ are as --NR₈ R₁₀ they may togetherwith the nitrogen form a a 5 to 7 membered ring comprised only of carbonatoms or carbon atoms and at least one heteroatom selected from O, N, orS;

R₉ is C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₃₋₇ cycloalkyl, C₄₋₆ cycloalkenyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, each of which may beunsubstituted or substituted by one or more fluorine atoms, or two R₉terms appearing as NR₉ R₉ may together with the nitrogen form a 5 to 7membered ring comprised only of carbon atoms or carbon atoms and atleast one heteroatom selected from O, N, or S;

R₁₀ is OR₈ or R₈ ;

R₁₁ is C₁₋₄ alkyl unsubstituted or substituted by one to threefluorines;

R₁₂ is R₁₃, C₃₋₇ cycloalkyl, (2-, 3- or 4-pyridyl), pyrimidyl,pyrazolyl, (1- or 2-imidazolyl), pyrrolyl, piperazinyl, piperidinyl,morpholinyl, furanyl, (2- or 3-thienyl), quinolinyl, naphthyl, orphenyl;

R₁₃ is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl,tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl,oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings isconnected through a carbon atom and each may be unsubstituted orsubstituted by one or two C₁₋₂ alkyl groups;

R₁₄ is hydrogen or R₁₅ ; or when R₁₀ and R₁₄ are as NR₁₀ R₁₄ they maytogether with the nitrogen form a 5 to 7 membered ring comprised only ofcarbon atoms or carbon atoms and at least one heteroatom selected fromO, N, or S;

R₁₅ is --(CR₄ R₅)_(t) R₁₂ or C₁₋₆ alkyl wherein the R₁₂ or C₁₋₆ alkylgroup is unsubstituted or substituted by one or more times by methyl orethyl unsubstituted or substituted by one to three fluorines, --F, --Br,--Cl, --NO₂, --Si(R₄)₂, --NR₈ R₁₀, --C(O)R₈, --C(O)OR₈, --O(CH₂)_(q) R₈,--CN, --C(O)NR₈ R₁₀, --O(CH₂)_(q) C(O)NR₈ R₁₀, --O(CH₂)_(q) C(O)R₈,--NR₁₀ C(O)NR₈ R₁₀, --NR₁₀ C(O)R₈, --NR₁₀ C(O)OR₉, --NR₁₀ C(O)R₁₃,--C(NR₁₀)NR₈ R₁₀, --C(NCN)NR₈ R₁₀, --C(NCN)SR₁₁, --NR₁₀ C(NCN)SR₁₁,--NR₁₀ C(NCN)NR₁₀ R₈, --NR₁₀ S(O)₂ R₉, --S(O)_(m') R₁₁, --NR₁₀C(O)C(O)NR₈ R₁₀, --NR₁₀ C(O)C(O)R₁₀, or R₁₃ ;

t is 0, 1, or 2;

provided that:

f) when q is 1 in OC(O)(O)_(q) R₇, then R₇ is not hydrogen; or thepharmaceutically acceptable salts thereof.

This invention also relates to the pharmaceutical compositionscomprising a compound of the invention and a pharmaceutically acceptablecarrier or diluent.

The invention also relates to a method of mediation or inhibition of theenzymatic activity (or catalytic activity) of PDE IV in mammals,including humans, which comprises administering to a mammal in needthereof an effective amount of a compound of the invention as shownbelow.

The invention further provides a method for the treatment of allergicand inflammatory disease which comprises administering to a mammal,including humans, in need thereof, an effective amount of a compound ofthe invention.

The invention also provides a method for the treatment of asthma whichcomprises administering to a mammal, including humans, in need thereof,an effective amount of a compound of the invention.

This invention also relates to a method of inhibiting TNF production ina mammal, including humans, which method comprises administering to amammal in need of such treatment, an effective TNF inhibiting amount ofa compound of the invention. This method may be used for theprophylactic treatment or prevention of certain TNF mediated diseasestates amenable thereto.

This invention also relates to a method of treating a human afflictedwith a human immunodeficiency virus (HIV), which comprises administeringto such human an effective TNF inhibiting amount of a compound of theinvention.

Compounds of the invention are also useful in the treatment ofadditional viral infections, where such viruses are sensitive toupregulation by TNF or will elicit TNF production in vivo.

In addition, compounds of the invention are also useful in treatingyeast and fungal infections, where such yeast and fungi are sensitive toupregulation by TNF or will elicit TNF production in vivo.

DETAILED DESCRIPTION OF THE INVENTION

This invention also relates to a method of mediating or inhibiting theenzymatic activity (or catalytic activity) of PDE IV in a mammal in needthereof and to inhibiting the production of TNF in a mammal in needthereof, which comprises administering to said mammal an effectiveamount of a compound of the invention.

Phosphodiesterase IV inhibitors are useful in the treatment of a varietyof allergic and inflammatory diseases including: asthma, chronicbronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergicconjunctivitis, vernal conjunctivitis, eosinophilic granuloma,psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis,Crohn's disease, reperfusion injury of the myocardium and brain, chronicglomerulonephritis, endotoxic shock and adult respiratory distresssyndrome. In addition, PDE IV inhibitors are useful in the treatment ofdiabetes insipidus and central nervous system disorders such asdepression and multi-infarct dementia.

The viruses contemplated for treatment herein are those that produce TNFas a result of infection, or those which are sensitive to inhibition,such as by decreased replication, directly or indirectly, by the TNFinhibitors of the invention. Such viruses include, but are not limitedto HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza, adenovirusand the Herpes group of viruses, such as, but not limited to, Herpeszoster and Herpes simplex.

This invention more specifically relates to a method of treating amammal, afflicted with a human immunodeficiency virus (HIV), whichcomprises administering to such mammal an effective TNF inhibitingamount of a compound of the invention.

The compounds of this invention may also be used in association with theveterinary treatment of animals, other than in humans, in need ofinhibition of TNF production. TNF mediated diseases for treatment,therapeutically or prophylactically, in animals include disease statessuch as those noted above, but in particular viral infections. Examplesof such viruses include, but are not limited to feline immunodeficiencyvirus (FIV) or other retroviral infection such as equine infectiousanemia virus, caprine arthritis virus, visna virus, maedi virus andother lentiviruses.

The compounds of this invention are also useful in treating yeast andfungal infections, where such yeast and fungi are sensitive toupregulation by TNF or will elicit TNF production in vivo. A preferreddisease state for treatment is fungal meningitis. Additionally, thecompounds of the invention may be administered in conjunction with otherdrugs of choice for systemic yeast and fungal infections. Drugs ofchoice for fungal infections, include but are not limited to the classof compounds called the polymixins, such as Polymycin B, the class ofcompounds called the imidazoles, such as clotrimazole, econazole,miconazole, and ketoconazole; the class of compounds called thetriazoles, such as fluconazole, and itranazole, and the class ofcompound called the Amphotericins, in particular Amphotericin B andliposomal Amphotericin B.

The compounds of the invention may also be used for inhibiting and/orreducing the toxicity of an anti-fungal, anti-bacterial or anti-viralagent by administering an effective amount of a compound of theinvention to a mammal in need of such treatment. Preferably, a compoundof the invention is administered for inhibiting or reducing the toxicityof the Amphotericin class of compounds, in particular Amphotericin B.

The term "C₁₋₃ alkyl", "C₁₋₄ alkyl", "C₁₋₆ alkyl" or "alkyl" groups asused herein is meant to include both straight or branched chain radicalsof 1 to 10, unless the chain length is limited thereto, including, butnot limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,isobutyl, tert-butyl, and the like. "Alkenyl" means both straight orbranched chain radicals of 1 to 6 carbon lengths, unless the chainlength is limited thereto, including but not limited to vinyl,1-propenyl, 2-propenyl, 2-propynyl, or 3-methyl-2-propenyl.

The term "cycloalkyl" or "cycloalkyl alkyl" means groups of 3-7 carbonatoms, such as cyclopropyl, cyclopropylmethyl, cyclopentyl, orcyclohexyl.

"Aryl" or "aralkyl", unless specified otherwise, means an aromatic ringor ring system of 6-10 carbon atoms, such as phenyl, benzyl, phenethyl,or naphthyl. Preferably the aryl is monocyclic, i.e, phenyl. The alkylchain is meant to include both straight or branched chain radicals of 1to 4 carbon atoms.

"Heteroaryl" means an aromatic ring system containing one or moreheteroatoms, such as imidazolyl, triazolyl, oxazolyl, pyridyl,pyrimidyl, pyrazolyl, pyrrolyl, furanyl, or thienyl.

"Halo" means all halogens, i.e., chloro, fluoro, bromo, or iodo."Inhibiting the production of IL-1" or "inhibiting the production ofTNF" means:

a) a decrease of excessive in vivo IL-1 or TNF levels, respectively, ina human to normal levels or below normal levels by inhibition of the invivo release of IL-1 by all cells, including but not limited tomonocytes or macrophages;

b) a down regulation, at the translational or transcriptional level, ofexcessive in vivo IL-1 or TNF levels, respectively, in a human to normallevels or below normal levels; or

c) a down regulation, by inhibition of the direct synthesis of IL- 1 orTNF levels as a postranslational event.

The phrase "TNF mediated disease or disease states" means any and alldisease states in which TNF plays a role, either by production of TNFitself, or by TNF causing another cytokine to be released, such as butnot limited to IL-1 or IL-6. A disease state in which IL-1, for instanceis a major component, and whose production or action, is exacerbated orsecreted in response to TNF, would therefore be considered a diseasestate mediated by TNF. As TNF-β (also known as lymphotoxin) has closestructural homology with TNF-α (also known as cachectin), and since eachinduces similar biologic responses and binds to the same cellularreceptor, both TNF-α and TNF-β are inhibited by the compounds of thepresent invention and thus are herein referred to collectively as "TNF"unless specifically delineated otherwise. Preferably TNF-α is inhibited.

"Cytokine" means any secreted polypeptide that affects the functions ofcells, and is a molecule which modulates interactions between cells inimmune, inflammatory, or hematopoietic responses. A cytokine includes,but is not limited to, monokines and lymphokines regardless of whichcells produce them.

The cytokine inhibited by the present invention for use in the treatmentof a HIV-infected human must be a cytokine which is implicated in (a)the initiation and/or maintenance of T cell activation and/or activatedT cell-mediated HIV gene expression and/or replication, and/or (b) anycytokine-mediated disease associated problem such as cachexia or muscledegeneration. Preferrably, his cytokine is TNF-α.

All of the compounds of the invention are useful in the method ofinhibiting the production of TNF, preferably by macrophages, monocytesor macrophages and monocytes, in a mammal, including humans, in needthereof. All of the compounds of the invention are useful in the methodof inhibiting or mediating the enzymatic or catalytic activity of PDE IVand in treatment of disease states mediated thereby.

Pharmaceutically acceptable salts of the instant compounds, where theycan be prepared, are also intended to be covered by this invention.These salts will be ones which are acceptable in their application to apharmaceutical use. By that it is meant that the salt will retain thebiological activity of the parent compound and the salt will not haveuntoward or deleterious effects in its application and use in treatingdiseases.

Preferred compounds are as follows as independently applied to Formula(I) or (II)!:

When R₁ is an alkyl substituted by 1 or more halogens, the halogens arepreferably fluorine and chlorine, more preferably a C₁₋₄ alkylsubstituted by 1 or more fluorines. The preferred halo-substituted alkylchain length is one or two carbons, and most preferred are the moieties--CF₃, --CH₂ F, --CHF₂, --CF₂ CHF₂, --CH₂ CF₃, and --CH₂ CHF₂. PreferredR₁ substitutents for the compounds of the invention are CH₂-cyclopropyl, CH₂ --C₅₋₆ cycloalkyl, C₄₋₆ cycloalkyl unsubstituted orsubstituted with OH, C₇₋₁₁ polycycloalkyl, (3- or 4-cyclopentenyl),phenyl, tetrahydrofuran-3-yl, benzyl or C₁₋₂ alkyl unsubstituted orsubstituted by 1 or more fluorines, --(CH₂)₁₋₃ C(O)O(CH₂)₀₋₂ CH₃,--(CH₂)₁₋₃ O(CH₂)₀₋₂ CH₃, and --(CH₂)₂₋₄ OH.

When R₁ term contains the moiety (CR₄ R₅), the R₄ and R₅ terms areindependently hydrogen or alkyl. This allows for branching of theindividual methylene units as (CR₄ R₅)_(n) or (CR₄ R₅)_(m) ; eachrepeating methylene unit is independent of the other, e.g., (CR₄ R₅)_(n)wherein n is 2 can be --CH₂ CH(--CH₃)--, for instance. The individualhydrogen atoms of the repeating methylene unit or the branchinghydrocarbon can unsubstituted or be substituted by fluorine independentof each other to yield, for instance, the preferred R₁ substitutions, asnoted above.

When R₁ is a C₇₋₁₁ polycycloalkyl, examples are bicyclo 2.2.1 !-heptyl,bicyclo 2.2.2!octyl, bicyclo 3.2.1 !octyl, tricyclo 5.2.1.0²,6 !decyl,etc. additional examples of which are described in Saccamano et al, WO87/06576, published 5 Nov. 1987.

W is preferably alkyl, alkenyl or alkynyl of 2 to 4 carbon atoms, andwhere it is alkenyl or alkynyl, that one or two double or triple bondsbe present. It is most preferred that W is 1,3-butadiynyl.

Z is preferably OR₉, O(S)₂ R₉ and NR₉ R₉. Most preferred are OR₉, O(S)₂R₉.

Preferred Z' is COOR₁₄.

Preferred X groups for the invention are those wherein X is YR₂ and Y isoxygen. The preferred X₂ group for the invention is that wherein X₂ isoxygen. The preferred X₃ group for The is that wherein X₃ is hydrogen.Preferred R₂ groups, where applicable, is a C₁₋₂ alkyl unsubstituted orsubstituted by 1 or more halogens. The halogen atoms are preferablyfluorine and chlorine, more preferably fluorine. More preferred R₂groups are those wherein R₂ is methyl, or the fluoro-substituted alkyls,specifically a C₁₋₂ alkyl, such as a --CF₃, --CHF₂, or --CH₂ CHF₂moiety. Most preferred are the --CHF₂ and --CH₃ moieties.

Preferred R₁₅ moieties include unsubstituted or substituted --(CH₂)₁₋₂(cyclopropyl), --(CH₂)₀₋₂ (cyclobutyl), --(CH₂)₀₋₂ (cyclopentyl)unsubstituted or substituted by OH, --(CH₂)₀₋₂ (cyclohexyl), --(CH₂)₀₋₂(2-, 3- or 4-pyridyl), (CH₂)₁₋₂ (2-imidazolyl), (CH₂)₂ (4-morpholinyl),(CH₂)₂ (4-piperazinyl), (CH₂)₁₋₂ (2-thienyl), (CH₂)₁₋₂ (4-thiazolyl),and (CH₂)₀₋₂ phenyl.

Preferred rings when R₈ and R₁₀ in the moiety --NR₈ R₁₀ and when R₉ inthe moiety NR₉ R₉ together with the nitrogen to which they are attachedform a 5 to 7 membered ring comprised of carbon or carbon and at leastone heteroatom selected from O, N, or S include, but are not limited to1-imidazolyl, 2-(R₈)-1-imidazolyl, 1-pyrazolyl, 3-(R₈)-1-pyrazolyl,1-triazolyl, 2-triazolyl, 5-(R₈)-1-triazolyl, 5-(R₈)-2-triazolyl,5-(R₈)-1-tetrazolyl, 5-(R₈)-2-tetrazolyl, 1-tetrazolyl, 2-tetrazloyl,morpholinyl, piperazinyl, 4-(R₈)-1-piperazinyl, or pyrrolyl ring.

Preferred groups for NR₈ R₁₄ which contain a heterocyclic ring are5-(R₁₄)-1-tetrazolyl, 2-(R₁₄)-1-imidazolyl, 5-(R₁₄)-2-tetrazolyl,4-(R₁₄)-1-piperazinyl, or 4-(R₁₅)-1-piperazinyl.

Preferred rings for R₁₃ include (2-, 4- or 5-imidazolyl), (3-, 4- or5-pyrazolyl), (4- or 5-triazolyl 1,2,3!), (3- or 5-triazolyl 1,2,4!),(5-tetrazolyl), (2-, 4-or 5-oxazolyl), (3-, 4- or 5-isoxazolyl), (3- or5-oxadiazolyl 1,2,4!), (2-oxadiazolyl 1,3,4!), (2-thiadiazolyl 1,3,4!),(2-, 4-, or 5-thiazolyl), (2-, 4-, or 5-oxazolidinyl), (2-, 4-, or5-thiazolidinyl), or (2-, 4-, or 5-imidazolidinyl).

Most preferred are those compounds wherein R₁ is --CH₂ -cyclopropyl,cyclopentyl, 3-hydroxycyclopentyl, methyl or CF₂ H; X is YR₂ ; Y isoxygen; X₂ is oxygen; X₃ is hydrogen; and R₂ is CF₂ H or methyl, W is1,3-butadiynyl.

The exemplified compounds are:

1,4-bis- { 3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-en-1-yltrifluoromethylsulfonato!-3-yl }buta-1,3-diyne, and 1,4-bis-{3-(3-cyclopentyloxy-4-methoxyphenyl)-1-methoxycyclohex-1-en!-3-yl}buta-1,3-diyne.

It will be recognized that some of the compounds of the invention mayexist in both racemic and optically active forms; some may also exist indistinct diastereomeric forms possessing distinct physical andbiological properties. All of these compounds are considered to bewithin the scope of the present invention.

Pharmaceutically acceptable salts are prepared in a standard manner. Theparent compound, dissolved in a suitable solvent, is treated with anexcess of an organic or inorganic acid, in the case of acid additionsalts of a base, or an excess of organic or inorganic base where themolecule contains a COOH for example.

Pharmaceutical compositions of the present invention comprise apharmaceutical carrier or diluent and some amount of a compound of theinvention. The compound may be present in an amount to effect aphysiological response, or it may be present in a lesser amount suchthat the user will need to take two or more units of the composition toeffect the treatment intended. These compositions may be made up as asolid, liquid or in a gaseous form. Or one of these three forms may betransformed to another at the time of being administered such as when asolid is delivered by aerosol means, or when a liquid is delivered as aspray or aerosol.

The nature of the composition and the pharmaceutical carrier or diluentwill, of course, depend upon the intended route of administration, forexample parenterally, topically, orally or by inhalation.

For topical administration the pharmaceutical composition will be in theform of a cream, ointment, liniment, lotion, pastes, aerosols, and dropssuitable for administration to the skin, eye, ear, or nose.

For parenteral administration the pharmaceutical composition will be inthe form of a sterile injectable liquid such as an ampule or an aqueousor non-aqueous liquid suspension.

For oral administration the pharmaceutical composition will be in theform of a tablet, capsule, powder, pellet, atroche, lozenge, syrup,liquid, or emulsion.

When the pharmaceutical composition is employed in the form of asolution or suspension, examples of appropriate pharmaceutical carriersor diluents include: for aqueous systems, water; for non-aqueoussystems, ethanol, glycerin, propylene glycol, corn oil, cottonseed oil,peanut oil, sesame oil, liquid parafins and mixtures thereof with water;for solid systems, lactose, kaolin and mannitol; and for aerosolsystems, dichlorodifluoromethane, chlorotrifluoroethane and compressedcarbon dioxide. Also, in addition to the pharmaceutical carrier ordiluent, the instant compositions may include other ingredients such asstabilizers, antioxidants, preservatives, lubricants, suspending agents,viscosity modifiers and the like, provided that the additionalingredients do not have a detrimental effect on therapeutic action ofthe instant compositions.

The pharmaceutical preparations thus described are made following theconventional techniques of the pharmaceutical chemist as appropriate tothe desired end product.

In these compositions, the amount of carrier or diluent will vary butpreferably will be the major proportion of a suspension or solution ofthe active ingredient. When the diluent is a solid it may be present inlesser, equal or greater amounts than the solid active ingredient.

Usually a compound of formula I is administered to a subject in acomposition comprising a nontoxic amount sufficient to produce aninhibition of the symptoms of a disease in which leukotrienes are afactor. Topical formulations will contain between about 0.01 to 5.0% byweight of the active ingredient and will be applied as required as apreventative or curative agent to the affected area. When employed as anoral, or other ingested or injected regimen, the dosage of thecomposition is selected from the range of from 50 mg to 1000 mg ofactive ingredient for each administration. For convenience, equal doseswill be administered 1 to 5 times daily with the daily dosage regimenbeing selected from about 50 mg to about 5000 mg.

No unacceptable toxicological effects are expected when these compoundsare administered in accordance with the present invention.

The following examples are given to further illustrate the describedinvention. These examples are intented solely for illustrating theinvention and should not be read to limit the invention in any manner.Reference is made to the claims for what is reserved to the inventorshereunder.

METHODS OF PREPARATION

Synthetic Scheme(s) With Textual Description

Some compounds of Formula (I), wherein W is a 1,3-butadiyne and whereinA and B represent Z as defined in relation to Formula (I) or a groupconvertible to Z, may be prepared by the processes disclosed hereinwhich comprise, for example, coupling of a molecule of the Formula1-Scheme 1 with a molecule of the Formula 2-Scheme 1 using anappropriate metal salt, such as cupric acetate, in a suitable solvent,such as DMF or pyridine, or a combination, such aspyridine/methanol/water, as in the method of Eglington and Galbraith (J.Chem. Soc., 1959, 889), to provide a compound of the Formula 3-Scheme 1.##STR3##

Alternatively, compounds of the Formula (I), wherein W and Z represent Wand Z as defined in relation to Formula (I) or a group convertible to Wor Z, may be prepared from the corresponding ketones as, e.g., compound1-Scheme 3, by the synthetic procedures described in co-pending U.S.application Ser. No. 08/130346 filed 1 Oct. 1993 and PCT applicationPCT/US94/10817.₋₋ ; syntheses of such ketone starting materials aredescribed in co-pending U.S. application Ser. No. 08/130215 and PCTapplication PCT/US94/10815 filed 23 Sep. 1994. ##STR4##

Some compounds of Formula (II), wherein W is a 1,3-butadiyne and whereinZ and Z' represents Z and Z' as defined in relation to Formula (II) or agroup convertible to Z or Z', may be prepared by the processes disclosedherein which comprise, for example, coupling of a molecule of theFormula 1-Scheme 3 with a molecule of the Formula 2-Scheme 3 using anappropriate metal salt, such as cupric acetate, in a suitable solvent,such as DMF or pyridine, or a combination, such as pyridine/methanolwater, as in the method of Eglington and Galbraith (J. Chem. Soc., 1959,889), to provide a compound of the Formula 3-Scheme 3. ##STR5##

Alternatively, compounds of the Formula (II), wherein W, Z and Z'represent W, Z and Z' as defined in relation to Formula (II) or a groupconvertible to W, Z or Z', may be prepared from the correspondingketones as, e.g., compound 1-Scheme 4, by the synthetic proceduresdescribed in co-pending U.S. application Ser. No. 08/130346 filed 1 Oct.1993 and PCT application PCT/US94/10817.₋₋ ; syntheses of such ketonestarting materials are described in co-pending U.S. application Ser. No.08/130215 and PCT application PCT/US94/10815 filed 23 Sep. 1994.##STR6##

Preparation of the remaining compounds of the Formulas (I) and (II) maybe accomplished by procedures analogous to those described above and inthe Examples, infra.

It will be recognized that compounds of the Formulas (Ia), (Ib) and (II)may exist in distinct diastereomeric forms possessing distinct physicaland biological properties; such isomers may be separated by standardchromatographic methods.

SYNTHETIC EXAMPLES Example 1

Preparation of 1,4-bis-{3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-en-1-yltrifluoromethylsulfonatol!-3-yl}buta-1,3-diyne

To a solution of diisopropylamine (1.95 mL, 13.9 mmol) intetrahydrofuran (12 mL) at 0° C. under an argon atmosphere is addedn-butyllithium (5.8 mL of 2.5M solution, 14.15 mmol), the resultingsolution is stirred for 25 min and then is cooled to -78° C. To this isadded a solution of 1,4-bis-{3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-on!-3-yl}buta-1,3-diyne!(2.07 g, 3.32 mmol, prepared by the procedures described in co-pendingU.S. patent application filed on even day herewith and identified asP50286) in tetrahydrofuran (9 mL). The resulting mixture is stirred at-78° C. for 2 h, at which time N-phenyltrifluoromethylsulfonimide (4.98g, 13.9 mmol) is added. The mixture is allowed to warm slowly to roomtemperature and after 5 h, the mixture is poured into water andextracted with methylene chloride. The organic extract is dried(potassium carbonate) and concentrated under reduced pressure. Theresidue is purified by flash chromatography.

Example 2

Preparation of 1,4-bis-{3-(3-cyclopentyloxy-4-methoxyphenyl)-1-methoxycyclohex-1-en!-3-yl}buta-1,3-diyne

To a solution of 1,4-bis-{3-(3-cyclopentyloxy4-methoxyphenyl)cyclohexan-1-on!-3-yl}buta-1,3-diyne!(0.3 g, 0.48 mmol) in dimethylformamide (3 mL) at 0° C. under an argonatmosphere is added potassium t-butoxide (0.11 g, 0.96 mmol) and, 0.5 hlater, dimethyl sulfate (0.09 mL, 0.96 mmol). After 5 min, ammoniumchloride is added, the mixture is extracted three times with ether, theorganic extract is washed three times with water, once with brine, isdried (magnesium sulfate) and is evaporated. Purification by flashchromatography provides the title compound.

UTILITY EXAMPLES Example A

Inhibitory effect of compounds of the invention on in vitro TNFproduction by human monocytes

The inhibitory effect of compounds of the invention on in vitro TNFproduction by human monocytes may be determined by the protocol asdescribed in Badger et al., EPO published Application 0 411 754 A2, Feb.6, 1991, and in Hanna, WO 90/15534, Dec. 27, 1990.

Example B

Two models of endotoxic shock have been utilized to determine in vivoTNF activity for the compounds of the invention. The protocol used inthese models is described in Badger et al, EPO published Application 0411 754 A2, Feb. 6, 1991, and in Hanna, WO 90/15534, Dec. 27, 1990.

The compound of Example 1 herein demonstrated a positive in vivoresponse in reducing serum levels of TNF induced by the injection ofendotoxin.

Example C

Isolation of PDE Isozymes

The phosphodiesterase inhibitory activity and selectivity of thecompounds of the invention can be determined using a battery of fivedistinct PDE isozymes. The tissues used as sources of the differentisozymes are as follows: 1) PDE Ib, porcine aorta; 2) PDE Ic, guinea-pigheart; 3) PDE III, guinea-pig heart; 4) PDE IV, human monocyte; and 5)PDE V (also called "Ia"), canine trachealis. PDEs Ia, Ib, Ic and III arepartially purified using standard chromatographic techniques Torphy andCieslinski, Mol. Pharmacol., 37:206-214, 1990!. PDE IV is purified tokinetic homogeneity by the sequential use of anion-exchange followed byheparin-Sepharose chromatography Torphy et al., J. Biol. Chem.,267:1798-1804, 1992!.

Phosphodiesterase activity is assayed as described in the protocol ofTorphy and Cieslinski, Mol. Pharmacol., 37:206-214, 1990. Positive IC₅₀'s in the nanomolar to μM range for compounds of the workings examplesdescribed herein for the invention have been demonstrated.

What is claimed is:
 1. A compound of Formula (Ia) or (Ib) ##STR7##wherein: R₁ is --(CR₄ R₅)_(n) C(O)O(CR₄ R₅)_(m) R₆, --(CR₄ R₅)_(n)C(O)NR₄ (CR₄ R₅)_(m) R₆, --(CR₄ R₅)_(n) O(CR₄ R₅)_(m) R₆, or --(CR₄R₅)_(r) R₆ wherein the alkyl moieties are unsubstituted or substitutedwith one or more halogens;m is 0 to 2; n is 0 to 4; r is 0 to 6; R₄ andR₅ are independently hydrogen or a C₁₋₂ alkyl; R₆ is hydrogen, methyl,hydroxyl, aryl, halo substituted aryl, aryloxyC₁₋₃ alkyl, halosubstituted aryloxyC₁₋₃ alkyl, indanyl, indenyl, C₇₋₁₁ polycycloalkyl,tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl,tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C₃₋₆cycloalkyl, or a C₄₋₆ cycloalkyl containing one or two unsaturatedbonds, wherein the cycloalkyl or heterocyclic moiety may beunsubstituted or substituted by 1 to 3 methyl groups, one ethyl group oran hydroxyl group;provided that: a) when R₆ is hydroxyl, then m is 2; orb) when R₆ is hydroxyl, then r is 2 to 6; or c) when R₆ is2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or2-tetrahydrothienyl, then m is 1 or 2; or d) when R₆ is2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or2-tetrahydrothienyl, then r is 1 to 6; e) when n is 1 and m is 0, thenR₆ is other than H in --(CR₄ R₅)_(n) O(CR₄ R₅)_(m) R₆ ; X is YR₂,fluorine, NR₄ R₅, or formyl amine; Y is O or S(O)_(m') ; m' is 0, 1, or2; X₂ is O or NR₈ ; X₃ is hydrogen or X; R₂ is --CH₃ or --CH₂ CH₃unsubstituted or substituted by 1 or more halogens; s is 0 to 4; W isalkyl of 2 to 6 carbons, alkenyl of 2 to 6 carbons or alkynyl of 2 to 6carbons; Z is S(O)_(m') R₉, OS(O)₂ R₉, OR₉, OC(O)NR₇ R₇, OC(O)(O)_(q)R₇, O(CR₄ R₅)_(n) OR₉, or NR₉ R₉ ; q is 0 or 1; R₇ is hydrogen or R₉ ;R₈ is hydrogen or C₁₋₄ alkyl unsubstituted or substituted by one tothree fluorines, or when R₈ and R₁₀ are as --NR₈ R₁₀ they may togetherwith the nitrogen form a a 5 to 7 membered ring comprised only of carbonatoms or carbon atoms and at least one heteroatom selected from O, N, orS; R₉ is C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₃₋₇ cycloalkyl, C₄₋₆ cycloalkenyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, each of which may beunsubstituted or substituted by one or more fluorine atoms, or two R₉terms appearing as NR₉ R₉ may together with the nitrogen form a 5 to 7membered ring comprised only of carbon atoms or carbon atoms and atleast one heteroatom selected from O, N, or S; R₁₀ is OR₈ or R₈;provided that: f) when q is 1 in OC(O)(O)_(q) R₇, then R₇ is nothydrogen; or the pharmaceutically acceptable salts thereof.
 2. Acompound of Formula (II): ##STR8## wherein: R₁ is --(CR₄ R₅)_(n)C(O)O(CR₄ R₅)_(m) R₆, --(CR₄ R₅)_(n) C(O)NR₄ (CR₄ R₅)_(m) R₆, --(CR₄R₅)_(n) O(CR₄ R₅)_(m) R₆, or --(CR₄ R₅)_(r) R₆ wherein the alkylmoieties are unsubstituted or substituted with one or more halogens;m is0 to 2; n is 0 to 4; r is 0 to 6; R₄ and R₅ are independently hydrogenor a C₁₋₂ alkyl; R₆ is hydrogen, methyl, hydroxyl, aryl, halosubstituted aryl, aryloxyC₁₋₃ alkyl, halo substituted aryloxyC₁₋₃ alkyl,indanyl, indenyl, C₇₋₁₁ polycycloalkyl, tetrahydrofuranyl, furanyl,tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl,tetrahydrothiopyranyl, thiopyranyl, C₃₋₆ cycloalkyl, or a C₄₋₆cycloalkyl containing one or two unsaturated bonds, wherein thecycloalkyl or heterocyclic moiety may be unsubstituted or substituted by1 to 3 methyl groups, one ethyl group or an hydroxyl group;providedthat: a) when R₆ is hydroxyl, then m is 2; or b) when R₆ is hydroxyl,then r is 2 to 6; or c) when R₆ is 2-tetrahydropyranyl,2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl,then m is 1 or 2; or d) when R₆ is 2-tetrahydropyranyl,2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl,then r is 1 to 6; e) when n is 1 and m is 0, then R₆ is other than H in--(CR₄ R₅)_(n) O(CR₄ R₅)_(m) R₆ ; X is YR₂, fluorine, NR₄ R₅, or formylamine; Y is O or S(O)_(m') ; m' is 0, 1, or 2; X₂ is O or NR₈ ; X₃ ishydrogen or X; R₂ is --CH₃ or --CH₂ CH₃ unsubstituted or substituted by1 or more halogens; s is 0 to4; W is alkyl of 2 to 6 carbons, alkenyl of2 to 6 carbons or alkynyl of 2 to 6 carbons; Z is NHR₁₄, S(O)_(m') R₉,OS(O)₂ R₉, OR₉, OC(O)NR₇ R₇, OC(O)(O)_(q) R₇, O(CR₄ R₅)_(n) OR₉, or NR₉R₉ ; Z' is C(Y')R₁₄, C(O)OR₁₄, C(Y')NR₁₀ R₁₄, C(NR₁₀)NR₁₀ R₁₄, CN,C(NOR₈)R₁₄, C(NOR₁₄)R₈, C(NR₈)NR₁₀ R₁₄, C(NR₁₄)NR₈ R₈ C(NCN)NR₁₀ R₁₄,C(NCN)SR₁₁, (2-, 4- or 5-imidazolyl), (3-, 4- or 5-pyrazolyl), (4- or5-triazolyl 1,2,3!), (3- or 5-triazolyl 1,2,4!), (5-tetrazolyl), (2-, 4-or 5-oxazolyl), (3-, 4- or 5-isoxazolyl), (3- or 5-oxadiazolyl 1,2,4!),(2-oxadiazolyl 1,3,4!), (2-thiadiazolyl 1,3,4!), (2-, 4-, or5-thiazolyl), (2-, 4-, or 5-oxazolidinyl), (2-, 4-, or 5-thiazolidinyl),or (2-, 4-, or 5-imidazolidinyl); wherein all of the heterocylic ringsystems may be optionally substituted one or more times by R₁₄ ; Y' is Oor S; q is 0 or 1; R₇ is hydrogen or R₉ ; R₈ is hydrogen or C₁₋₄ alkylunsubstituted or substituted by one to three fluorines, or when R₈ andR₁₀ are as --NR₈ R₁₀ they may together with the nitrogen form a a 5 to 7membered ring comprised only of carbon atoms or carbon atoms and atleast one heteroatom selected from O, N, or S; R₉ is C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₃₋₇ cycloalkyl, C₄₋₆ cycloalkenyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, each of which may be unsubstituted orsubstituted by one or more fluorine atoms, or two R₉ terms appearing asNR₉ R₉ may together with the nitrogen form a 5 to 7 membered ringcomprised only of carbon atoms or carbon atoms and at least oneheteroatom selected from O, N, or S; R₁₀ is OR₈ or R₈ ; R₁₁ is C₁₋₄alkyl unsubstituted or substituted by one to three fluorines; R₁₂ isR₁₃, C₃₋₇ cycloalkyl, (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1-or 2-imidazolyl), pyrrolyl, piperazinyl, piperidinyl, morpholinyl,furanyl, (2- or 3-thienyl), quinolinyl, naphthyl, or phenyl; R₁₃ isoxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl,imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, orthiadiazolyl, and each of these heterocyclic rings is connected througha carbon atom and each may be unsubstituted or substituted by one or twoC₁₋₂ alkyl groups; R₁₄ is hydrogen or R_(15;) or when R₁₀ and R₁₄ are asNR₁₀ R₁₄ they may together with the nitrogen form a 5 to 7 membered ringcomprised only of carbon atoms or carbon atoms and at least oneheteroatom selected from O, N, or S; R₁₅ is --(CH₄ R₅)_(t) R₁₂ or C₁₋₆alkyl wherein the R₁₂ or C₁₋₆ alkyl group is unsubstituted orsubstituted by one or more times by methyl or ethyl unsubstituted orsubstituted by one to three fluorines, --F, --Br, --Cl, --NO₂,--Si(R₄)₂, --NR₈ R₁₀, --C(O)R₈, --C(O)OR₈, --O(CH₂)_(q) R₈, --CN,--C(O)NR₈ R₁₀, --O(CH₂)_(q) C(O)NR₈ R₁₀, --O(CH₂)_(q) C(O)R₈, --NR₁₀C(O)NR₈ R₁₀, --NR₁₀ C(O)R₈, --NR₁₀ C(O)OR₉, --NR₁₀ C(O)R₁₃, --C(NR₁₀)NR₈R₁₀, --C(NCN)NR₈ R₁₀, --C(NCN)SR₁₁, --NR₁₀ C(NCN)SR₁₁, --NR₁₀ C(NCN)NR₁₀R₈, --NR₁₀ S(O)₂ R₉, --S(O)_(m') R₁₁, --NR₁₀ C(O)C(O)NR₈ R₁₀, --NR₁₀C(O)C(O)R₁₀, or R₁₃ ; t is 0, 1, or 2;provided that: f) when q is 1 inOC(O)(O)_(q) R₇, then R₇ is not hydrogen; or the pharmaceuticallyacceptable salts thereof.
 3. A compound according to claim 1 whichis1,4-bis-{ 3-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-en-1-yltrifluoromethylsulfonato!-3-yl}buta-1,3-diyne, or 1,4-bis-{3-(3-cyclopentyloxy-4-methoxyphenyl)-1-methoxycyclohex-1-en!-3-yl}buta-1,3-diyne.
 4. A pharmaceutical composition comprising a compoundof Formula (Ia) or (Ib) according to claim 1 and a pharmaceuticallyacceptable excipient.